Regulation of human polymorphonuclear leukocyte superoxide release by cellular responses to chemotactic peptides.

Abstract

Abstract Cellular responses to chemotactic gradients may influence subsequent oxidative activation of neutrophils by inflammatory, infectious, or chemotactic stimuli. We compared superoxide release by human neutrophils in response to chemotactic, particulate, and soluble-non-chemotactic stimuli to assess the consequences of previous encounters with chemoattractants on oxidative responses. Superoxide release stimulated by otherwise optimal concentrations of the synthetic tripeptide N-for-myl-methionyl-leucyl-phenylalanine (FMLP) was inhibited or suppressed if neutrophils were first exposed to low concentrations of this chemoattractant. The amount of FMLP required to elicit maximal superoxide release was increased, and the amount of superoxide released in response to optimal concentrations of FMLP was decreased by prior exposure of neutrophils to chemotactically effective concentrations of the peptide. A similar time-dependent desensitization of oxidative responsiveness to FMLP was induced by exposure of neutrophils to low concentrations of complement-derived chemoattractants. The effect of chemoattractants on oxidative activation was both specific and reversible; neutrophils prein-cubated with FMLP responded with a normal or enhanced burst of superoxide generation when challenged with zymosan, digitonin, or fluoride. Removal or inactivation of the desensitizing agent was followed by a time- and temperature-dependent restoration of oxidative responsiveness to the chemotactic peptide, which indicated that desensitization was not due to irreversible alteration or depletion of any component of the superoxide-generating system. The hyporesponsive state induced by FMLP could not be attributed to soluble inhibitors generated during the interaction of FMLP with neutrophils. Neutrophil oxidative responses to chemotactic factors are susceptible to specific regulation by stimulus-dependent processes activated during initial encounters with chemoattractants. Such processes provide a mechanism for holding free radical release in abeyance until the site of infectious or inflammatory challenge is reached.